DESCRIPTION: This proposal describes a research program involving synthetic, mechanistic/mode of action, and biological studies of molecules with demonstrated or potential relevance to cancer research and treatment. The long-term objectives of this program are: (1) to elucidate the specific functions of microtubules in signal transduction pathways that regulate the cell cycle, and (2) to design and synthesize new molecules to probe, and ultimately control, the functions of microtubules in cells. The key question that we wish to address is: What is the cellular mechanism that induces cell cycle arrest and cell death in response to anticancer drugs such as taxol that bind to microtubules? The specific aims of this application are: (1) to determine if the cytotoxicit displayed by microtubule-binding drugs results from inhibition of microtubule dynamics, (2) to discover how cells monitor the integrity of microtubules, and (3) to synthesize and analyze new high-affinity microtubule ligands. The principal methodologies that we will employ are organic synthesis, protein biochemistry, and molecular biology. We will synthesize molecules that bind to microtubules, and these compounds will be examined as inhibitors of microtubul dynamics and as cytotoxic agents. Biochemical and genetic approaches will be used to identify proteins that display drug-dependent binding to microtubules. Results from these studies will provide insights into the cellular mechanisms of anticancer drugs such as taxol, a promising drug that is currently used to treat breast and ovarian cancers, and is in clinical trials for several additional cancers. These studies may not only illuminate basic mechanisms of cellular function but may ultimately point to new strategies for the treatment of human disease.